We have been studying clathrin-independent forms of endocytosis (CIE) and have identified a number of endogenous PM proteins that enter cells through this mechanism. We have begun to study these proteins in detail in an attempt to understand how they travel in cells and whether they specifically interact with cellular machinery. We have identified signals in the cytoplasmic tails of CD44, CD98 and CD147 that are responsible for their altered trafficking and are looking for cellular machinery that is responsible for recognition and sorting of these signals. Some of the cargo interacting proteins may associate with the cargo at the cell surface. Understanding how these proteins move into and out of cells is important because these proteins are involved in interaction with the extracellular matrix (CD44), are involved in nutrient transport (CD98) and interact with integrins and matrix metalloproteinases (CD147). To facilitate these studies we have used SNAP-tag technology to quantify endocytosis and recycling of specific cell surface proteins. We have screened FDA library compounds for those that inhibit or stimulate CIE and are following up on a promising candidate inhibitor. We have also been interested in examining the communication between CIE and clathrin-mediated endocytosis (CME).